Heterocyclic aminoalkylpyridine derivatives as psychopharmaceuticals

ABSTRACT

The invention relates to heterocyclic aminoalkylpyridine derivatives of the formula I: 
                 
 
where
     R 1  is the radical of a heterocycle having 1 to 3 ring structures, where each ring structure is saturated, unsaturated or aromatic and optionally fused to other ring structures to give a fused ring system and the heterocycle has a total of 1 to 4 N, O and/or S atoms in the ring structures and is optionally monosubstituted, disubstituted or trisubstituted by one or more of the groups -A, —OR 4 , —N(R 4 ) 2 , —NO 2 , —CN, Hal, —COOR 4 , —CON(R 4 ) 2 , —COR 4 , ═O;   R 2  is a phenyl group which is optionally monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted by one or more of the groups Hal, -A, —O-A, —NO 2  or —CN,
       or is a thienyl group which is optionally monosubstituted or disubstituted by one or more of the groups Hal, -A, —O-A, -NO 2 , —CN or thienyl;   
       R 3  is H, -A, —CO-A, —C(R 4 ) 2 R 2 , —C(R 4 ) 2 -pyridinediyl-R 2 ;   R 4  is H or -A;   A is C 1 -C 6 -alkyl, where 1 to 7 hydrogen atoms are optionally replaced by fluorine;   —X— is —O—, —S—, sulfinyl, sulfonyl, —C(R 4 ) 2 —;   —Y— is —[C(R 4 ) 2 ] n —;   —Z— is —C(R 4 ) 2 —;   Hal is F, Cl, Br or I;   n is 1, 2, 3 or 4;   and their tolerable salts and solvates and their use as medicaments.

The invention relates to heterocyclic aminoalkylpyridine derivatives,their preparation and their use as psychopharmaceuticals.

The heterocyclic aminoalkylpyridine derivatives can be represented bythe general formula I:

where

-   R¹ is the radical of a heterocycle having 1 to 3 ring structures,    where each ring structure is saturated, unsaturated or aromatic and    optionally fused to other ring structures to give a fused ring    system and the heterocycle has a total of 1 to 4 N, O and/or S atoms    in the ring structures and is optionally monosubstituted,    disubstituted or trisubstituted by one or more of the groups -A,    —OR⁴, —N(R⁴)₂, —NO₂, —CN, Hal, —COOR⁴, —CON(R⁴)₂, —COR⁴, ═O;-   R² is a phenyl group which is optionally monosubstituted,    disubstituted, trisubstituted, tetrasubstituted or pentasubstituted    by one or more of the groups Hal, -A, —O-A, —NO₂ or —CN, or is a    thienyl group which is optionally monosubstituted or disubstituted    by one or more of the groups Hal, -A, —O-A, —NO₂, —CN or thienyl;-   R³ is H, -A, —CO-A, —C(R⁴)₂R², —C(R⁴)₂-pyridinediyl-R²;-   R⁴ is H or -A;-   A is C₁-C₆-alkyl, where 1 to 7 hydrogen atoms are optionally    replaced by fluorine;-   —X— is —O—, —S—, sulfinyl, sulfonyl, —C(R⁴)₂—;-   —Y— is —[C(R⁴)₂]_(n)—;-   —Z— is —C(R⁴)₂—;-   Hal is F, Cl, Br or I;-   n is 1, 2, 3 or 4;-   and their tolerable salts and solvates.

Psychoses, which also include diseases of the schizophrenia type, havebeen attributed to a hyperactivity of the limbic dopamine system (Snyderet al., Science 184: 1243-1253, 1974). The antipsychotic effect ofneuroleptics has been attributed to their D₂-antagonistic properties(with regard to the nomenclature of the receptors: Basic Neurochemistry,Editors: G. J. Siegel, B. W. Agranoff, R. W. Albers, P. B. Molinoff, 5thedition, Raven Press, Ltd., N. Y. USA, Chapters 12 and 13; otherwise thefollowing technical publications: Creese et al., Science 192: 481-483,1976; Farde et al., Psychopharmacology 99: 28-31, 1989; Feeman et al.,Nature 261: 717-719, 1976; Wiesel et al., Prog. Neuro-Psychopharmacol. &Biol. Psychiat. 14: 759-767, 1990). Consequently, the classical dopaminehypothesis of schizophrenia was formulated, according to whichneuroleptics have to bind to the D₂ receptor. On account of theirextrapyramidal side effects, the employment of classical D₂ antagonistsis severely restricted, especially in the case of chronicadministration. The extrapyramidal side effects include, for example,tremor, akinesia, dystonia and akathisia (Cavallaro & Smeraldi, CNSDrugs 4: 278-293, 1995). There are only a few antipsychotics which causesignificantly fewer or no extrapyramidal side effects at all and whichare described as “atypical neuroleptics” (Kervin, Brit. J. Psychiatry1964, 141-148, 1994). The prototype atypical neuroleptic clozapine hasextremely low extrapyramidal side effects, but causes other seriouscomplications such as agranulocytosis, which sometimes is fatal (Alviret al., New Engl. J. Med. 329: 162-167, 1993).

Because 5-HT_(1A) agonists intensify antipsychotic properties ofconventional dopamine D₂ antagonists in animals (Wadenberg & Ahlenios,J. Neural. Transm. 74: 195-198, 1988) and prevent the catalepsy inducedby dopamine D₂ antagonists (Costall et al., Neuropharmacology 14:859-868, 1975), 5-HT_(1A)-agonistic properties could be advantageous.The efficacy of buspirone, a pharmacon having 5-HT_(1A)-agonistic anddopamine D₂-antagonistic properties, has been demonstrated inschizophrenia patients (Goff et al., J. Clin, Psychopharmacol. 11:193-197, 1991). Apart from various dopamine autoreceptor agonists whichalso have a significant affinity for the 5-HT_(1A) receptor (e.g.U-86170F, Lahti et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 344:509-513, 1991), PD1431188 (Melzer et al., J. Pharmacol. Exp. Ther. 274:912-920, 1995) and roxindole (Bartoszyk et al., J. Pharmacol., Exp.Ther. 276: 41-48, 1996), only a few dopamine D₂ antagonists have beendeveloped which also have an affinity for the 5-HT_(1A) receptor, suchas mazapertine (Reiz et al., J. Mid. Chem. 37: 1060-1062, 1994), S16924(Millan et al., Br. J. Pharmacol. 114: 156 B, 1995) or ziprasidone(Seeger et al., J. Pharmacol. Exp. Ther. 275: 101-113, 1995). Thesealready known compounds have disadvantages with respect to affinity orspecificity. Thus mazapertine also shows an affinity for the α₁receptor. S16924 additionally has 5-HT_(2A/C)-antagonistic propertiesand ziprasidone moreover binds to the 5-HT_(1D/2A/2C) receptors.

It is the object of the invention to make available medicaments, inparticular psychopharmaceuticals. It is a further object of theinvention to make available compounds which bind both to the dopamine D₂receptor and to the 5-HT_(1A) receptor.

This object is achieved by the compounds of the general formula I and bytheir tolerable salts and solvates (see above).

Their binding properties can be determined by known 5-HT_(1A)(serotonin) binding test and dopamine binding tests (5-HT_(1A)(serotonin) binding test: Matzen et al., J. Med. Chem., 43, 1149-1157,(2000) in particular page 1156 with reference to Eur. J. Pharmacol.:140, 143-155 (1987); dopamine binding tests: Böttcher et al., J. Med.Chem.: 35, 4020-4026, (1992) with reference to J. Neurochem.: 46,1058-1067 (1986)).

These compounds differ both from the aforementioned atypicalneuroleptics and from the amino(thio)ethers disclosed in EP-A 0 707 007,of the formula:

where R⁰ to R⁹, X and Z have the meanings defined in EP-A 0 707 007.

The compounds according to the invention can be employed for thetreatment of diseases which are associated with the serotinin anddopamine neurotransmitter system and in which high-affinity serotininreceptors (5-HT_(1A) receptors) and/or dopamine D₂ receptors areinvolved. The most important indication for the administration of thecompound of the general formula I are psychoses of any type, inparticular also mental disorders of the schizophrenia type. Moreover,the compounds can also be employed for the prevention of cognitivefunctional disorders, i.e. for improvement of the learning ability andof the memory. The compounds of the general formula I are also suitablefor the control of the symptoms of Alzheimer's disease. The substancesof the general formula I according to the invention are moreoversuitable for the prophylaxis and control of cerebral infarcts (cerebralapoplexy), such as cerebral stroke and cerebral ischemia. The substancesare also suitable for the treatment of disorders such as pathologicalanxiety states, overexcitation, hyperactivity and attention disorders inchildren and adolescents, deep-seated developmental disorders anddisorders of social behavior with mental retardation, depression,compulsive disorders in the narrower (OCD) and wider sense (OCSD),certain sexual function disorders, sleep disorders and eating disorders,and also such psychiatric symptoms in the context of senile dementia anddementia of the Alzheimer type, i.e. diseases of the central nervoussystem in the widest sense.

The compounds of the general formula I and their tolerable salts andsolvates can thus be employed as active ingredients of medicaments suchas anxiolytics, antidepressants, neuroleptics and/or antihypertensives.

-   R¹ is an optionally substituted heterocycle having 1 to 3 ring    structures. The number of ring structures of a heterocycle is    identical to the number of ring openings which imaginarily have to    be carried out in order to convert the heterocycle into an acyclic    compound. The ring structures can be independent of one another, if    that is chemically possible, saturated, unsaturated or aromatic. A    ring structure can optionally be fused to other ring structures to    give a fused ring system. Nonaromatic saturated or unsaturated ring    structures can also be connected to one another in analogy to fused    ring systems, that is share bonds with one another, as is the case,    for example, with steroids or with chroman. The heterocycle    comprises a total of 1 to 4 nitrogen, oxygen and/or sulfur atoms,    which replace the carbon atoms in the ring structures. Preferably,    these N, O and/or S atoms are not adjacent. The heterocycle is    optionally monosubstituted, disubstituted or trisubstituted by one    or more of the groups -A, —OR⁴, N(R⁴)₂, —NO₂, —CN, Hal, —COOR⁴,    —CON(R⁴)₂, —COR⁴, ═O. R¹ is preferably quinolyl, isoquinolyl, which    optionally has at least one chlorine substituent, or indolyl,    benzothiazolyl, coumaronyl, coumarinyl, pyridyl or carbazolyl, where    optionally at least one hydrogen of the quinolyl, isoquinolyl,    indolyl or benzothiazolyl is replaced by a methyl group or    ethoxycarbonyl group. In particular, R¹ carries the meaning    quinolin-7-yl, quinolin-8-yl, where a hydrogen is optionally    replaced by a chlorine atom in position 5, or indol-4-yl or    indol-7-yl, where a hydrogen in position 2 of the quinolyl or    indolyl is optionally replaced by a methyl group or ethoxycarbonyl    group. The meanings indol-4-yl, 2-methylindol-4-yl and quinolin-8-yl    are particularly preferred for R¹.-   R² is a phenyl group which is optionally monosubstituted,    disubstituted, trisubstituted, tetrasubstituted or pentasubstituted    by one or more groups Hal, -A, —O-A-, —NO₂ or —CN—R² can further    carry the meaning of a thienyl group which is optionally    monosubstituted or disubstituted by one or more of the groups Hal,    -A, —O-A-, NO₂, —CN or thienyl. R² is preferably fluorophenyl,    difluorophenyl, cyanophenyl or tolyl. In particular, R² has the    meaning fluorophenyl, 2,4-difluorophenyl, 3-cyanophenyl or    4-methylphenyl.-   R³ carries the meaning H, -A, —CO-A-, —C(R⁴)₂R²,    —C(R⁴)₂-pyridinediyl-R²:

The meaning R³ equal to H is preferred.

-   R⁴ carries the meaning H or -A, where H is preferred.-   A is C₁-C₆-alkyl, where 1 to 7 hydrogen atoms are optionally    replaced by fluorine. A can be branched or unbranched and is    preferably methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,    tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-,    1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or    4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl,    1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl,    1,1,2- or 1,2,2-trimethylpropyl. Methyl, ethyl, isopropyl, n-propyl,    n-butyl or tert-butyl is particularly preferred for A.-   —X— can assume the meaning —O—, —S—, sulfinyl, sulfonyl or —C(R⁴)₂—,    where the meaning oxygen (—O—) is preferred.-   —Y— is —[C(R⁴)₂]_(n)—, in particular ethylene (—CH₂—CH₂—).-   —Z— has the meaning —C(R⁴)₂—, in particular methylene (—CH₂—).-   Hal is F, Cl, Br or I where F and Cl, in particular F, are    preferred.-   n is 1, 2, 3 or 4, where n equal to 2 is preferred.

The substituents R¹, R², R³, X, Y, Z can independently of one anotherassume one of the aforementioned meanings. If, in R¹, R², R³, X, Y, Z,the meaning of one of the terms assumes substituents containing R⁴, A,Hal or n, R⁴, A, Hal and n can have another meaning in any substituentR¹, R², R³, X, Y, Z. The compounds of the general formula I are all themore highly preferred, the more their substituents have preferredmeanings and the more highly these meanings are preferred.

A preferred compound of the general formula I is described by thegeneral formula VIII, where Z is methylene, Y is ethylene, R³ is H and Xis oxygen and Z and X are in the meta-position relative to the pyridinenitrogen:

If the compounds of the general formula I are optically active, theformula I includes both any isolated optical antipodes and thecorresponding optionally racemic mixtures in any conceivablecomposition.

A compound of the general formula I can be converted into thecorresponding salt (that is acid addition salt) using an acid. Acidswhich afford the tolerable (that is biocompatible and adequatelybioavailable) salts are suitable for this reaction. It is thus possibleto use inorganic acids such as sulfuric acid or hydrohalic acids such ashydrochloric acid, bromic acid or phosphoric acids such asorthophosphoric acid, nitric acid, sulfamic acid, aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylicacids, sulfonic acids or sulfuric acid derivatives such as formic acid,acetic acid, pronionic acid, pivalic acid diethylacetic acid, malonicacid, succinic acid, pimelic acid, fumaric acid, maleic acid, lacticacid, tartaric acid, malic acid, benzoic acid, salicylic acid,2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid,nicotinic acid, isonicotinic acid, methanesulfonic acid orethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, paratoluenesulfonic acid,naphthalenemonosulfonic acid and naphthalenedisulfonic acid and sulfuricacid lauryl ester.

If desired, the corresponding free bases of the general formula I can beliberated by the treatment of their salts with strong bases such assodium hydroxide, potassium hydroxide or sodium or potassium carbonate,provided that no other acidic groups are present in the molecule. In thelast-mentioned cases, in which the compounds of the general formula Icarry free acidic groups, salt formation can also be brought about bytreatment with strong bases. Suitable bases are alkali metal hydroxides,alkaline earth metal hydroxides, or organic bases in the form ofprimary, secondary or tertiary amines.

Solvates of the compounds of the general formula I are understood asmeaning adducts of chemically “inert” solvent molecules to the compoundsof the formula I which are formed on account of their mutual attractiveforce. Solvates are, for example, mono- and dihydrates or additioncompounds with alcohols such as methanol or ethanol.

It is known that pharmaceuticals can be converted synthetically intoderivatives (for example into alkyl or acyl derivatives, into sugar oroligopeptide derivatives and others) which are converted back into theactive compounds of the general formula I in the body metabolically byextracellular or intracellular enzymes. The invention also relates tosuch “prodrug derivatives” of the compounds of the general formula I.

A further subject of the invention is the use of a compound of thegeneral formula I or of one of its tolerable salts or solvates for theproduction of a medicament which is suitable for the treatment of humanor animal disorders, in particular of disorders of the central nervoussystem such as pathological anxiety states, depression and/or psychoses,for the prevention of side effects during the treatment of high bloodpressure (e.g. with α-methyldopa), for the treatment of endocrinologicaland/or gynecological disorders, e.g. for the treatment of acromegaly,hypogonadism, secondary amenorrhea, the post-menstrual syndrome andundesired lactation in puberty and for the prophylaxis and therapy ofcerebral disorders (e.g. of migraine), in particular in geriatrics, in asimilar manner to specific ergot alkaloids and for the control andprophylaxis of cerebral infarct (cerebral apoplexy) such as cerebralstroke and cerebral ischemia. Moreover, the pharmaceutical preparationsand medicaments which contain a compound of the general formula I aresuitable for improvement of the cognitive functional ability and for thetreatment of Alzheimer's disease symptoms. In particular, suchmedicaments are suitable for the treatment of mental disorders of theschizophrenia type and for the control of psychotic anxiety states. Theterm treatment in the context of the invention includes prophylaxis andtherapy of human or animal diseases.

The substances of the general formula I are normally administeredanalogously to known, commercially obtainable pharmaceuticalpreparations (e.g. of bromocriptine and dihydroergocornine), preferablyin doses of between 0.2 and 500 mg, in particular of between 0.2 and 15mg per dose unit. The daily dose unit is between 0.001 and 10 mg per kgof body weight. Low doses (of between 0.2 and 1 mg per dose unit, 0.001to 0.005 mg per kg of body weight) are particularly suitable forpharmaceutical preparations for the treatment of migraine. A dose ofbetween 10 and 50 mg per dose unit is preferred for other indications.However, the dose to be administered depends on a large number offactors, e.g. on the efficacy of the corresponding component, the age,the body weight and the general condition of the patient.

A further subject of the invention is a process for the production of apharmaceutical preparation, which comprises the conversion of a compoundof the general formula I or of one of its tolerable salts or solvates toa suitable dose form together with a suitable vehicle. The compounds ofthe general formula I can be brought into a suitable dose form togetherwith at least one vehicle or excipient, if appropriate in combinationwith a further active ingredient.

Suitable vehicles are organic or inorganic substances which are suitablefor enteral (e.g. oral) or parenteral or topical administration andwhich do not react with the substances of the general formula Iaccording to the invention. Examples of such vehicles are water,vegetable oils, benzyl alcohols, polyethylene glycols, gelatin,carbohydrates such as lactose and starch, magnesium stearate, talc andraw petroleum jelly. Tablets, coated tablets, capsules, syrups, juices,drops or suppositories are in particular employed for enteraladministration. Solutions, preferably oily or aqueous solutions, such assuspensions, emulsions or alternatively implants are used for parenteraladministration. Ointments, creams or powders are employed in the case ofexternal application. The compounds of the general formula I can also belyophilized and the resulting lyophilizates processed to give injectablepreparations.

The invention further relates to medicaments which contain at least onecompound of the general formula I or one of its tolerable salts orsolvates and, if appropriate, further ingredients such as vehicles,excipients etc. These preparations can be employed as medicaments forthe treatment of human or animal diseases.

The aforementioned medicaments can be sterilized and processed togetherwith excipients such as lubricants, preservatives, stabilizers and/orwetting agents, emulsifiers, osmotically active substances, buffers,colorants or flavor enhancers to give other pharmaceutical preparations.

A further subject of the invention is a process for the preparation ofthe compounds of the general formula I. This process is suitable forcompounds in which the substituent Z is in the meta-position relative tothe nitrogen of the pyridine ring connected to Z and in which Z has themeaning of methylene.

In a first step, bromopyridin-3-ylmethanal (VII) is reacted withH₂N—Y—OH and, for example, sodium borohydride to give a compound of thegeneral formula VI. In a second step, the secondary amine of the generalformula VI is provided with a protective group. This is carried out withaddition of reagents of the formula L-CO—O—K, where K has the meaning oftert-butyl, fluoren-9-ylmethyl or benzyl and L is either Cl, N₃ ortert-butoxycarbonyloxy. Compounds of the general formula V are reactedwith suitable boronic acid derivatives (R²—B(OH)₂) using an appropriatePd(0) catalyst, compounds of the formula IV resulting in which thebromine atom is replaced by the R² substituent (Suzuki coupling, cf. A.Suzuki, N. Miyaura Chem. Rev. 1995, 95, 2457-2483; A. R. Martin, Y.Yang, Acta Chem. Scand. 1993, 47, 221-230). With the aid of theMitsunobu reaction, compounds of the general formula IV are reacted withcompounds of the formula HX—R¹, compounds of the formula III resulting.Details of the named reaction can be taken from: Mitsunobu, Bull. Chem.Soc. Jpn.: 40, 4235-4238 (1967); Hughes, Org. React.: 42, 335-656(1992); Mitsunobu, Synthesis, 1-28 (1981); Hughes et al., J. Am. Chem.Soc.: 110, 6487-6491 (1988); Crich et al., J. Org. Chem.: 54, 257-259(1989); Camp et al., J. Org. Chem.: 54, 3045-3049, 3049-3054 (1989). Theprotective group is then removed from compounds of the general formulaIII, compounds of the general formula II resulting. By means ofalkylation reactions known to the person skilled in the art,substituents R³ can be introduced into compounds of the general formulaII.

Alternatively, the synthesis is carried out via the followingintermediates:

The invention likewise relates to this alternative process. By means ofthe Suzuki reaction, a bromopyridylmethanol of the formula XII iscoupled to a boronic acid derivative R²—B(OH)₂ under Pd(0) catalysis(Suzuki coupling, cf. A. Suzuki, N. Miyaura Chem. Rev. 1995, 95,2457-2483; A. R. Martin, Y. Yang, Acta Chem. Scand. 1993, 47, 221-230).The alcohol of the formula XI resulting here is oxidized, e.g. with MnO₂in tetrahydrofuran, to the corresponding aldehyde of the formula X. Thisis reacted with an amine (R¹—O—Y—NH₂) with formation of a Schiffs base,which is immediately reduced to the corresponding secondary amine. Thesecondary amine can be alkylated to give the tertiary amine by knownreactions, whereby the substituent R³ is introduced into the molecule.

The amine can be prepared in various ways. In a preferred embodiment, itis identical with amines of the general formula XIII. m can assumevalues of between 1 and 3. The amine of the formula XIII is formed byalkylation of an alcohol R¹—OH with a nitrile of the formula XV withformation of a nitrile of the formula XIV and subsequent reduction tothe corresponding primary amine.

A synthesis scheme for the compounds in which Z is not methyleneincludes the following steps:

-   -   Suzuki coupling (analogously to Example 2, see also A.        Suzuki, N. Miyaura Chem. Rev. 1995, 95, 2457-2483; A. R.        Martin, Y. Yang, Acta Chem. Scand. 1993, 47, 221-230);    -   Deprotonation with lithium diisopropylamide (LDA) and        alkylation, fresh deprotonation and fresh alkylation        (compare G. A. Molander et al. J. Org. Chem. 58, 1993,        7216-7227);    -   Hydrolysis using NaOH;    -   Curtius rearrangement (compare R. J. Sundberg, S. Jiang, Org.        Prep. Proced. Int. 29, 1997, 117-122);    -   Alkylation with methyl bromoacetate (analogously to Example 2);    -   Reduction of the ester to the aldehyde with diisobutylaluminum        hydride (DIBAH, compare J. Svoboda, J. Palecek, Collect. Czech.        Chem. Commun. 56, 1991, 1317-1332);    -   Coupling of amine and aldehyde by reductive amination        (analogously to Example 2).

A further subject of the invention are compounds of the general formulaeII, III, IV, V and VI, the substituents having the meanings alreadymentioned.

A further subject of the invention are compounds of the general formulaIX, the substituents having the meanings already mentioned.

The invention is described by the following examples.

The molecular weight (M+H⁺) is determined with the aid of electron sprayionization mass spectroscopy. The mass-spectroscopic data derive fromHPLC/MSC runs (HPLC coupled with an electrospray ionization massspectrometer). The numerical values are, as customary in this procedure,not the molecular weights of the unmodified compounds, but the molecularweights of the protonated compounds (below: M+H⁺). The method isdescribed in the following references:

-   M. Yamashita, J. B. Fenn, J. Phys. Chem. 88, 1984, 4451-4459; C. K.    Meng et al., Zeitschrift für Physik D 10, 1988, 361-368; J. B. Fenn    et al., Science 246, 1989, 64-71.

EXAMPLE 1

Preparation of the Compound5-[(3-fluorophenyl)pyridin-3-ylmethyl]-[2-(2-methyl-1-H-indol-4-yloxy)ethyl]aminedihydrochloride.

The synthesis follows the synthesis scheme where the bromine atom of theformula VII is in the meta position relative to the pyridine nitrogen,R² is 3-fluorophenyl, Y is ethylene, X has the meaning of oxygen and R¹is 2-methylindol-4-yl.

A solution of 113 g (607 mmol) of 5-bromopyridine-3-carbaldehyde, 41.9ml (700 mmol) of ethanolamine and 12 g (10 mmol) of toluene-4-sulfonicacid monohydrate in 1 l of toluene is heated in a water separator for 5hours. After cooling, 500 ml of methanol are added to the solution and78.8 g (2.00 mol) of sodium borohydride are introduced in portions withstirring. The reaction mixture is stirred at room temperature for 18hours, concentrated in vacuo and the residue is partitioned betweenwater and ethyl acetate. The organic phase is evaporated:2-[(5-bromopyridin-3-ylmethyl)amino]ethanol ((M+H⁺)=231.233) as aslightly yellowish oil which is employed for the next reaction withoutfurther purification.

A solution of 164 g (750 mmol) of di-tert-butyl dicarbonate in 1 l ofdichloromethane is slowly added dropwise to a solution of 120 g (about519 mmol) of crude 2-[(5-bromopyridin-3-ylmethyl)amino]ethanol in 1 l ofdichloromethane cooled to 0° C. The reaction mixture is stirred at roomtemperature for 18 hours, treated with 3 l of water and the organicphase is separated off. The organic phase is dried over sodium sulfateand concentrated, and the residue is chromatographed on a silica gelcolumn using dichloromethane/methanol 9:1: tert-butyl(5-bromopyridin-3-ylmethyl)-(2-hydroxyethyl)carbamate ((M+H⁺)=331.333)as a yellowish oil. A solution of 5.40 g (16.3 mmol) of tert-butyl(5-bromopyridin-3-ylmethyl)-(2-hydroxyethyl)carbamate, 4.6 g (32.9 mmol)of 3-fluorobenzeneboronic acid, 250 g (0.27 mmol) oftris(dibenzylideneacetone)dipalladium(0) and 220 mg (1.09 mmol) oftri-tert-butylphosphine in 200 ml of dioxane is treated with 10.6 g(32.5 mmol) of cesium carbonate and stirred at 100° C. for 4 hours. Thereaction mixture is added to water and extracted with ethyl acetate. Theorganic phase is evaporated and the residue is chromatographed on asilica gel column using petroleum ether/ethyl acetate as eluent:tert-butyl[5-(3-fluorophenyl)pyridin-3-ylmethyl]-(2-hydroxyethyl)carbamate((M+H⁺)=347) as a colorless oil.

A solution of 100 mg (0.289 mmol) of tert-butyl[5-(3-fluorophenyl)pyridin-3-ylmethyl]-(2-hydroxyethyl)carbamate and86.8 mg (0.590 mmol) of 4-hydroxy-2-methylindole in 5 ml of THF istreated with 240 mg of polymer-bound triphenylphosphine and stirred atroom temperature for 10 minutes. 166 mg (720 mmol) of di-tert-butylazodicarboxylate are then added and the mixture is stirred at roomtemperature for 18 hours. 1 g of strongly basic ion exchanger is thenadded, and the mixture is stirred for 1 hour and filtered. The filtrateis evaporated. The following compound is obtained: tert-butyl[5-(3-fluorophenyl)pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)ethyl]carbamate((M+H⁺)=476) as a yellowish oil.

The crude tert-butyl[5-(3-fluorophenyl)pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)ethyl]carbamateobtained in the previous example is treated with 2 ml of 4N hydrogenchloride in dioxane, diluted with 1 ml of methanol and stirred at roomtemperature for 2 hours. The reaction mixture is evaporated, and theresidue is stirred with diethyl ether and filtered. The residue ispartitioned between 1 N sodium hydroxide solution and ethyl acetate, theorganic phase is evaporated and the residue is treated with an excess of0.1 N HCl in isopropanol. The solvent is distilled off:5-(3-fluorophenyl)pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)ethyl]aminedihydrochloride as a brownish solid, (M+H⁺)=376.

EXAMPLE 2

Preparation of the Compound5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(1H-indol-4-yloxy)ethyl]aminehydrochloride by an Alternative Synthesis Method.

A solution of 244 g (1.30 mol) of (5-bromopyridin-3-yl)methanol and 200g (1.43 mol) of 4-fluorobenzeneboronic acid in 1.5 l of toluene istreated with 750 ml of water, 168 g (2.00 mol) of sodiumhydrogencarbonate and 5.0 g (4.3 mmol) oftetrakis(triphenylphosphine)palladium(0) and heated to boiling for 24hours. The organic phase is separated off, dried over sodium sulfate andevaporated. The residue is recrystallized from tert-butyl methyl ether:[5-(4-fluorophenyl)pyridin-3-yl]methanol as colorless crystals of m.p.71-72° C.

A solution of 62.0 g (305 mmol) of[5-(4-fluorophenyl)pyridin-3-yl]methanol in 500 ml of THF is treatedwith 135 g (1.554 mol) of manganese dioxide and stirred at 45° C. for 18hours. The reaction mixture is filtered and the filtrate is evaporated.The residue is recrystallized from tert-butyl methyl ether:5-(4-fluorophenyl)pyridine-3-carbaldehyde as colorless crystals; (M+H⁺)202.

A solution of 1.00 g (7.51 mmol) of 4-hydroxyindole and 965 mg (7.80mmol) of bromoacetonitrile in 30 ml of acetonitrile is treated with 2.6g (8.0 mmol) of cesium carbonate and stirred at room temperature for 18hours. The reaction mixture is filtered and the filtrate is evaporated:(1H-indol-4-yloxy)acetonitrile as a gray solid; (M+H⁺): 173.

A solution of 1.20 g (6.97 mmol) of (1H-indol-4-yloxy)acetonitrile in 20ml of THF cooled to 0° C. is treated with 531 mg (14.0 mmol) of lithiumaluminum hydride and warmed to room temperature with stirring. Afterstirring at room temperature for 2 hours, the reaction mixture istreated with 2 g of sodium sulfate moistened with water and filtered.The filtrate is evaporated: 2-(1H-indol-4-yloxy)ethylamine as ayellowish oil; (M+H⁺): 177.

700 mg (3.972 mmol) of 2-(1H-indol-4-yloxy)ethylamine and 100 mg (0.52mmol) of toluene-4-sulfonic acid monohydrate are added to a solution of805 mg (4.00 mmol) of 5-(4-fluorophenyl)pyridine-3-carbaldehyde in 80 mlof toluene and the mixture is heated to boiling for 18 hours in a waterseparator. After cooling, the mixture is treated with 50 ml of methanoland 630 mg (16.0 mmol) of sodium borohydride are added. The reactionmixture is stirred at room temperature for 18 hours, concentrated invacuo and the residue is partitioned between water and ethyl acetate.The organic phase is evaporated and the residue is chromatographed on asilica gel column using ethyl acetate/ethanol 8:2 as eluent:[5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(1H-indol-4-yloxy)-ethyl]amineas colorless crystals; (M+H⁺) 362. The product thus obtained is treatedwith 3 ml of 0.1 N HCl in isopropanol and stirred at room temperaturefor one hour. The solvent is distilled off, and the residue is treatedwith diethyl ether and filtered:[5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(1H-indol-4-yloxy)ethyl]aminehydrochloride as brownish crystals; (M+H⁺) 362.

EXAMPLE 3

The following compounds are prepared analogously.

No. Structure Name or salt form (M + H⁺) a

[5-(4-fluorophenyl)-pyridin-3- ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)ethyl]amine hydrochloride 376 b

[2-(5-chloroquinoline-8- yloxy)ethyl]-[5-(2,4- difluorophenyl)pyridin-3-ylmethyl]amine hydrochloride 426 c

[5-(2,4-difluorophenyl)- pyridin-3-ylmethyl]-[2-(2- methylquinolin-8-yloxy)ethyl]amine hydrochloride 406 d

[5-(2,4-difluorophenyl)- pyridin-3-ylmethyl]-[2-(quinolin-8-yloxy)ethyl]amine hydrochloride 392 e

[2-(5-chloroquinolin-8- yloxy)ethyl]-[5-(4- fluorophenyl)pyridin-3-ylmethyl]amine hydrochloride 408 f

[5-(4-fluorophenyl)-pyridin-3- ylmethyl]-[2-(2- methylquinolin-8-yloxy)ethyl]amine hydrochloride 388 g

[5-(4-fluorophenyl)-pyridin-3- ylmethyl]-[2-(quinolin-8-yloxy)-ethyl]amine hydrochloride 374 h

[5-(3-fluorophenyl)-pyridin-3- ylmethyl]-[2-(quinolin-8-yloxy)-ethyl]amine hydrochloride 374 i

[5-(3-fluorophenyl)-pyridin-3- ylmethyl]-[2-(2- methylquinolin-8-yloxy)ethyl]amine hydrochloride 388 j

[2-(5-chloroquinolin-8- yloxy)ethyl]-[5-(3- fluorophenyl)pyridin-3-ylmethyl]amine hydrochloride 408 k

[5-(2,4-difluorophenyl)- pyridin-3-ylmethyl]-[2-(2- methyl-1H-indol-4-yloxy)ethyl]amine hydrochloride 394 l

[5-(3-fluorophenyl)-pyridin-3- ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)ethyl]amine hydrochloride 376 m

[5-(2,4-difluorophenyl)- pyridin-3-ylmethyl]-[2- (quinolin-7-yloxy)-ethyl]amine hydrochloride 392 n

[5-(3-fluorophenyl)-pyridin-3- ylmethyl]-[2-(quinolin-7-yloxy)-ethyl]amine hydrochloride 374 o

[5-(4-fluorophenyl)-pyridin-3- ylmethyl]-[2-(quinolin-7-yloxy)-ethyl]amine hydrochloride 374 p

[5-(4-fluorophenyl)-pyridin-3- ylmethyl]-[2-(2- methylbenzothiazol-5-yloxy)ethyl]amine dihydrochloride 394 q

[5-(4-fluorophenyl)-pyridin-3- ylmethyl]-[2-(quinolin-6-yloxy)-ethyl]amine trihydrochloride 374 r

[5-(4-fluorophenyl)-pyridin-3- ylmethyl]-[2-(isoquinolin-7-yloxy)-ethyl]amine trihydrochloride 374 s

[2-(benzo[1,2,5]thiadiazol-5- yloxy)ethyl]-[5-(4-fluorophenyl)-pyridin-3- ylmethyl]-amine dihydrochloride 381 t

[2-(9H-carbazol-4- yloxy)ethyl]-[5-(4- fluorophenyl)pyridin-3-ylmethyl]amine dihydrochloride 412 u

[2-(benzo[1,3]dioxol-5- yloxy)ethyl]-[5-(4- fluorophenyl)pyridin-3-ylmethyl]amine dihydrochloride 367 v

[2-(benzofuran-5- yloxy)ethyl][5-(4- fluorophenyl)pyridin-3-ylmethyl]amine dihydrochloride 363 w

[2-(chroman-6-yloxy)-ethyl]- [5-(4-fluorophenyl)pyridin-3-ylmethyl]amine dihydrochloride 448 x

[5-(3-fluorophenyl)-pyridin-3- ylmethyl]-[2-(2- methylbenzothiazol-5-yloxy)ethyl]amine dihydrochloride 394 y

[5-(3-fluorophenyl)-pyridin-3- ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)ethyl]amine dihydrochloride 376 z

[2-(2-methyl-benzothiazol-5- yloxy)-ethyl]-(5-p-tolylpyridin-3-ylmethyl)amine dihydrochloride 390 aa

3-(5-{[2-(2-methyl benzothiazol-5-yloxy)- ethylamino]methyl}-pyridin-3-yl)benzonitrile dihydrochloride 401 bb

[5-(2,4-difluorophenyl)- pyridin-3-ylmethyl]-[2-(2-methylbenzothiazol-5- yloxy)ethyl]amine dihydrochloride 412 cc

[5-(2,4-difluorophenyl)- pyridin-3-ylmethyl]-[2-(2- methyl-1H-indol-4-yloxy)ethyl]amine dihydrochloride 394 dd

[2-(2-methyl-1H-indol-4- yloxy)ethyl]-(5-p-tolylpyridin-3-ylmethyl)amine dihydrochloride 372 ee

ethyl 7-(2-{[5-(2,4- difluorophenyl)pyridin-3-ylmethyl]amino}-ethoxy)-1H- indol-2-carboxylate dihydrochloride 452 ff

ethyl 7-(2-{[5-(3- cyanophenyl)pyridin-3- ylmethyl]amino}-ethoxy)-1H-indol-2-carboxylate dihydrochloride 441 gg

ethyl 7-(2-{[5-(3- fluorophenyl)pyridin-3- ylmethyl]amino}-ethoxy)-1H-indol-2-carboxylate dihydrochloride 434 hh

ethyl 7-{2-[(5-p-tolyl-pyridin- 3-ylmethyl)-amino]ethoxy}-1H-indole-2-carboxylate dihydrochloride 413 ii

[5-(4-fluorophenyl)-pyridin-3- ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)ethyl]amine dihydrochloride 376 jj

6-(2-{[5-(4- fluorophenyl)pyridin-3- ylmethyl]amino}-ethoxy)chromen-2-one dihydrochloride 391 kk

[5-(4-fluorophenyl)-pyridin-3- ylmethyl]-[2-(pyridin-2-yloxy)ethyl]-amine trihydrochloride 324 ll

[5-(4-fluorophenyl)-pyridin-3- ylmethyl]-[2-(2- methylquinolin-8-yloxy)ethyl]amine trihydrochloride 388 mm

[5-(4-fluorophenyl)-pyridin-3- ylmethyl]-[2-(quinolin-8-yloxy)-ethyl]amine trihydrochloride 374 nn

[5-(4-fluorophenyl)-pyridin-3- ylmethyl]-[2-(isoquinolin-5-yloxy)-ethyl]amine trihydrochloride 374 oo

5-(2-{[5-(4- fluorophenyl)pyridin-3- ylmethyl]amino}-ethoxy)-1-methyl-1,3-dihydroindol-2- one dihydrochloride 392 pp

[5-(4-fluorophenyl)-pyridin-3- ylmethyl]-[2-(1H-indol-4-yloxy)-ethyl]amine hydrochloride 362 qq

[5-(3-fluorophenyl)-pyridin-3- ylmethyl]-[2-(1H-indol-4-yloxy)-ethyl]amine hydrochloride 362 rr

[5-(2,3-difluorophenyl)- pyridin-3-ylmethyl]-[2-(2- methyl-1H-indol-4-yloxy)ethyl]amine hydrochloride 394 ss

[5-(3,5-difluorophenyl)- pyridin-3-ylmethyl]-[2-(2- methyl-1H-indol-4-yloxy)ethyl]amine hydrochloride 394 tt

[5-(2,6-difluorophenyl)- pyridin-3-ylmethyl]-[2-(2- methyl-1H-indol-4-yloxy)ethyl]amine hydrochloride 394 uu

[5-(3,4-difluorophenyl)- pyridin-3-ylmethyl]-[2-(2- methyl-1H-indol-4-yloxy)ethyl]amine hydrochloride 394 vv

[2-(2-methyl-1H-indol-4- yloxy)ethyl]-[5-(3,4,5-trifluorophenyl)-pyridin-3- ylmethyl]-amine hydrochloride 412 ww

[5-(2,4-difluoro- phenyl)pyridin-3-ylmethyl]- [2-(1H-indol-4-yloxy)ethyl]amine hydrochloride 380 xx

[2-(2-methyl-1H-indol-4- yloxy)ethyl]-(5-phenylpyridin- 3-ylmethyl)aminehydrochloride 358 yy

[5-(2-fluorophenyl)-pyridin-3- ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)ethyl]amine hydrochloride 376 zz

[5-(3-fluorophenyl)-pyridin- 3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)-ethyl]- amine methanesulfonate 376 aaa

[5-(2,5-difluorophenyl)- pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)- ethyl]-amine hydrochloride 394 bbb

[5-(4-fluorophenyl)-pyridin- 3-ylmethyl]-[2-(1H-indol-7-yloxy)-ethyl]-amine hydrochloride 362 ccc

[5-(2,4-difluorophenyl)- pyridin-3-ylmethyl]-[2-(1H-indol-7-yloxy)-ethyl]-amine hydrochloride 380 ddd

[5-(3-fluorophenyl)-pyridin- 3-ylmethyl]-[2-(1H-indol-7-yloxy)-ethyl]amine hydrochloride 362 eee

[5-(3,4-difluorophenyl)- pyridin-3-ylmethyl]-[2-(1H-indol-4-yloxy)-ethyl]-amine hydrochloride 380 fff

[5-(3,5-difluorophenyl)- pyridin-3-ylmethyl]-[2-(1H-indol-4-yloxy)-ethyl]-amine hydrochloride 380 ggg

[5-(2,5-difluorophenyl)- pyridin-3-ylmethyl]-[2-(1H-indol-4-yloxy)-ethyl]-amine hydrochloride 380 hhh

[5-(3-fluorophenyl)-pyridin- 3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)-ethyl]- amine malonate 376 iii

[5-(3-fluorophenyl)-pyridin- 3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)-ethyl]- amine hemifumarate 376 jjj

[5-(3-fluorophenyl)-pyridin- 3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)-ethyl]- amine hemisulfate 376 kkk

[5-(3-fluorophenyl)-pyridin- 3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)-ethyl]- amine tartrate 376 lll

[5-(3,5-difluorophenyl)- pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)- ethyl]-amine hemifumarate 394 mmm

[5-(2-fluorophenyl)-pyridin- 3-ylmethyl]-[2-(1H-indol-4-yloxy)-ethyl]-amine dihydrochloride 362 nnn

[2-(1H-indol-4-yloxy)- ethyl]-[5-(3,4,5- trifluorophenyl)-pyridin-3-ylmethyl]-amine dihydrochloride 398 ooo

[2-(1H-indol-4-yloxy)- ethyl]-(5-phenyl-pyridin-3- ylmethyl)-aminedihydrochloride 344

EXAMPLE 4

Ampoules for Injection

A solution of 100 g of a compound of the general formula I and 5 g ofdisodium hydrogenphosphate is adjusted to pH 6.5 using 2 N hydrochloricacid in 3 l of double-distilled water, sterile filtered and filled intoinjection ampoules, and lyophilized. Sterile conditions were adhered tohere. Each injection ampoule contains 5 mg of the active component ofthe general formula I.

EXAMPLE 5

A mixture of 20 g of a compound of the general formula I is mixed with100 g of soya lecithin and 1400 g of cocoa butter with warming andpoured into hollows. Each suppository contains 20 mg of the activecomponent.

EXAMPLE 6

A solution comprising 1 g of a compound of the general formula I, 9.38 gof NaH₂PO₄×2 H₂O, 28.48 g of Na₂HPO₄×12 H₂O and 0.1 g of benzalkoniumchloride is prepared using 940 ml of double-distilled water. Thesolution is adjusted to pH 6.8 and made up to one liter withdouble-distilled water and sterilized by irradiation. This solution canbe used in the form of eye drops.

EXAMPLE 7

Ointment

500 mg of a compound of the general formula I are blended with 99.5 g ofraw petroleum jelly under aseptic conditions.

EXAMPLE 8

Tablets

100 g of a compound of the general formula I, 1 kg of lactose, 600 g ofmicrocrystalline cellulose, 600 g of cornstarch, 100 g ofpolyvinyl-pyrrolidone, 80 g of talc and 10 g of magnesium stearate aremixed and pressed in a customary manner to give tablets such that onetablet contains 100 mg of the active component.

EXAMPLE 9

Coated Tablets

Tablets are prepared as in Example 7 and then coated in a known mannerwith sucrose, maize starch, talc, tragacanth gum and colorants.

EXAMPLE 10

Capsules

Hard gelatin capsules are filled with a compound of the general formulaI in a known manner such that each capsule contains 5 mg of the activecomponent.

EXAMPLE 11

Inhalation Spray

14 g of a compound of the general formula I are dissolved in 10 l ofisotonic saline solution. The solution is filled into commerciallyobtainable spray containers which have a pump mechanism. The solutioncan be sprayed into the mouth or into the nose. One puff of spray(approximately 0.1 ml) corresponds to a dose of 0.14 mg of a compound ofthe general formula I.

1. A compound of the formula I

where R¹ is a heterocycle radical which is quinolyl or isoquinolyloptionally substituted by at least one chlorine, or indolyl,benzothiazolyl, coumaronyl, coumarinyl, pyridyl, or carbazolyl, whereinquinolyl, isoquinolyl, indolyl, or benzothiazolyl is optionallysubstituted with a methyl group or an ethoxycarbonyl group and theheterocycle radical is optionally monosubstituted, disubstituted ortrisubstituted by one or more of the groups -A, —OR⁴, —N(R⁴)₂, —NO₂,—CN, Hal, —COOR⁴, —CON(R⁴)₂, —COR⁴, or ═O; R² is a phenyl group which isoptionally monosubstituted, disubstituted, trisubstituted,tetrasubstituted or pentasubstituted by one or more of the groups Hal,-A, —O-A, —NO₂ or —CN, or is a thienyl group which is optionallymonosubstituted or disubstituted by one or more of the groups Hal, -A,—O-A, —NO₂, —CN or thienyl; R³ is H, -A, —CO-A, —C(R⁴)₂R², or—C(R⁴)₂-pyridinediyl-R²; R⁴ is H or —A; A is C₁-C₆-alkyl, where 1 to 7hydrogen atoms are optionally replaced by fluorine; —X— is —O—, —S—,sulfinyl, sulfonyl, or —C(R⁴)₂—; —Y— is —[C(R⁴)₂]_(n)—; —Z— is —C(R⁴)₂—;Hal is F, Cl, Br or I; and n is 1, 2, 3 or 4; or a salt or solvatethereof.
 2. A compound according to claim 1, wherein Z is in the metaposition relative to the nitrogen of the pyridine ring connected to Z.3. A compound according to claim 1, wherein: Z is methylene, Y isethylene, R³ is H, and/or X is oxygen.
 4. A compound according to claim1, wherein R² is in the meta position relative to the nitrogen of thepyridine ring connected to R².
 5. A compound according to claim 1,wherein: R¹ is quinolyl, isoquinolyl, which optionally has at least onechlorine substituent, or indolyl, benzothiazolyl, coumaronyl,coumarinyl, pyridyl or carbazolyl, where optionally at least onehydrogen of the quinolyl, isoquinolyl, indolyl or benzothiazolyl isreplaced by a methyl group or ethoxycarbonyl group; and/or R² isfluorophenyl, difluorophenyl, cyanophenyl or tolyl.
 6. A compoundaccording to claim 1, wherein: R¹ is quinolin-7-yl, quinolin-8-yl, wherea hydrogen is optionally replaced by a chlorine atom in position 5, orindol-4-yl or indol-7-yl, where a hydrogen in position 2 of the quinolylor indolyl is optionally replaced by a methyl group or ethoxycarbonylgroup; and/or R² is fluorophenyl, 2,4-difluorophenyl, 3-cyanophenyl or4-methylphenyl.
 7. A compound according to claim 1, of: a)[5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)-ethyl]aminehydrochloride b)[2-(5-chloroquinolin-8-yloxy)ethyl]-[5-(2,4-difluorophenyl)pyridin-3-ylmethyl]aminehydrochloride c)[5-(2,4-difluorophenyl)pyridin-3-ylmethyl]-[2-(2-methylquinolin-8-yloxy)ethyl]aminehydrochloride d)[5-(2,4-difluorophenyl)pyridin-3-ylmethyl]-[2-(quinolin-8-yloxy)ethyl]-aminehydrochloride e)[2-(5-chloroquinolin-8-yloxy)ethyl]-[5-(4-fluorophenyl)pyridin-3-ylmethyl]aminehydrochloride f)[5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(2-methylquinolin-8-yloxy)-ethyl]aminehydrochloride g)[5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(quinolin-8-yloxy)ethyl]-aminehydrochloride h)[5-(3-fluorophenyl)pyridin-3-ylmethyl]-[2-(quinolin-8-yloxy)ethyl]-aminehydrochloride i)[5-(3-fluorophenyl)pyridin-3-ylmethyl]-[2-(2-methylquinolin-8-yloxy)-ethyl]aminehydrochloride j)[2-(5-chloroquinolin-8-yloxy)ethyl]-[5-(3-fluorophenyl)pyridin-3-ylmethyl]aminehydrochloride k)[5-(2,4-difluorophenyl)pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)ethyl]aminehydrochloride l)[5-(3-fluorophenyl)pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)-ethyl]aminehydrochloride m)[5-(2,4-difluorophenyl)pyridin-3-ylmethyl]-[2-(quinolin-7-yloxy)ethyl]-aminehydrochloride n)[5-(3-fluorophenyl)pyridin-3-ylmethyl]-[2-(quinolin-7-yloxy)ethyl]-aminehydrochloride o)[5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(quinolin-7-yloxy)ethyl]-aminehydrochloride p)[5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(2-methylbenzothiazol-5-yloxy)ethyl]-aminedihydrochloride q)[5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(quinolin-6-yloxy)ethyl]-aminetrihydrochloride r)[5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(isoquinolin-7-yloxy)ethyl]-aminetrihydrochloride s)[2-(benzo[1,2,5]thiadiazol-5-yloxy)ethyl]-[5-(4-fluorophenyl)pyridin-3-ylmethyl]aminedihydrochloride t)[2-(9H-carbazol-4-yloxy)ethyl]-[5-(4fluorophenyl)pyridin-3-ylmethyl]-aminedihydrochloride u)[2-(benzo[1,3]dioxol-5-yloxy)ethyl]-[5-(4-fluorophenyl)pyridin-3-ylmethyl]-aminedihydrochloride v) [2-(benzofuran-5-yloxy)ethyl]-[5-(4-fluorophenyl)pyridin-3-ylmethyl]-amine dihydrochloride w)[2-(chroman-6-yloxy)ethyl]-[5-(4-fluorophenyl)pyridin-3-ylmethyl]-aminedihydrochloride x)[5-(3-fluorophenyl)pyridin-3-ylmethyl]-[2-(2-methylbenzothiazol-5-yloxy)ethyl]aminedihydrochloride y)[5-(3-fluorophenyl)pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)-ethyl]aminedihydrochloride z)[2-(2-methylbenzothiazol-5-yloxy)ethyl]-(5-p-tolylpyridin-3-ylmethyl)-aminedihydrochloride aa)3-(5-{[2-(2-methylbenzothiazol-5-yloxy)ethylamino]methyl}pyridin-3-yl)benzonitriledihydrochloride bb)[5-(2,4-difluorophenyl)pyridin-3-ylmethyl]-[2-(2-methylbenzothiazol-5-yloxy)ethyl]aminedihydrochloride cc)[5-(2,4-difluorophenyl)pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)ethyl]aminedihydrochloride dd)[2-(2-methyl-1H-indol-4-yloxy)ethyl]-(5-p-tolylpyridin-3-ylmethyl)-aminedihydrochloride ee) ethyl7-(2-{[5-(2,4-difluorophenyl)pyridin-3-ylmethyl]amino}ethoxy)-1H-indole-2-carboxylatedihydrochloride ff) ethyl7-(2-{[5-(3-cyanophenyl)pyridin-3-ylmethyl]amino}ethoxy)-1H-indole-2-carboxylatedihydrochloride gg) ethyl7-(2-{[5-(3-fluorophenyl)pyridin-3-ylmethyl]amino}ethoxy)-1H-indole-2-carboxylatedihydrochloride hh) ethyl7-{2-[(5-p-tolylpyridin-3-ylmethyl)amino]ethoxy}-1H-indole-2-carboxylatedihydrochloride ii)[5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(2methyl-1H-indol-4-yloxy)-ethyl]aminedihydrochloride kk)[5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(pyridin-2-yloxy)ethyl]-aminetrihydrochloride ll)[5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(methylquinolin-8-yloxy)-ethyl]aminetrihydrochloride mm)[5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(quinolin-8-yloxy)ethyl]-aminetrihydrochloride nn)[5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(isoquinolin-5-yloxy)ethyl]-aminetrihydrochloride oo)5-(2-{[5-(4-fluorophenyl)pyridin-3-ylmethyl]amino}ethoxy)-1-methyl-1,3-dihydroindol-2-onedihydrochloride pp)[5-(4-fluorophenyl)pyridin-3-ylmethyl]-[2-(1H-indol-4-yloxy)ethyl]-aminehydrochloride qq)[5-(3-fluorophenyl)pyridin-3-ylmethyl]-[2-(1H-indol-4-yloxy)ethyl]-aminehydrochloride rr)[5-(2,3-difluorophenyl)pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)ethyl]aminehydrochloride ss)[5-(3,5-difluorophenyl)pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)ethyl]aminehydrochloride tt)[5-(2,6-difluorophenyl)pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)ethyl]aminehydrochloride uu)[5-(3,4-difluorophenyl)pyridin-3-ylmethyl]-[2-(2methyl-1H-indol-4-yloxy)ethyl]aminehydrochloride vv)[2-(2-methyl-1H-indol-4-yloxy)ethyl]-[5-(3,4,5-trifluorophenyl)pyridin-3-ylmethyl]aminehydrochloride ww)[5-(2,4-difluorophenyl)pyridin-3-ylmethyl]-[2-(1H-indol-4-yloxy)-ethyl]aminehydrochloride xx)[2-(2-methyl-1H-indol-4-yloxy)ethyl]-(5-phenylpyridin-3-ylmethyl)-aminehydrochloride yy)[5-(2-fluorophenyl)pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)-ethyl]aminehydrochloride zz)[5-(3-fluorophenyl)-pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)-ethyl]-aminemethanesulfonate aaa)[5-(2,5-difluorophenyl)-pyridin-3-ylmethyl]-[2-(2-methyl-1-H-indol-4-yloxy)-ethyl]-aminehydrochloride bbb)[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-[2-(1H-indol-7-yloxy)-ethyl]-aminehydrochloride ccc)[5-(2,4-difluorophenyl)-pyridin-3-ylmethyl]-[2-(1H-indol-7-yloxy)-ethyl]-aminehydrochloride ddd)[5-(3-fluorophenyl)-pyridin-3-ylmethyl]-[2-(1H-indol-7-yloxy)-ethyl]-aminehydrochloride eee)[5-(3,4-difluorophenyl)-pyridin-3-ylmethyl]-[2-(1H-indol-4-yloxy)-ethyl]-aminehydrochloride fff)[5-(3,5-difluorophenyl)-pyridin-3-ylmethyl]-[2-(1H-indol-4-yloxy)-ethyl]-aminehydrochloride ggg)[5-(2,5-difluorophenyl)-pyridin-3-ylmethyl]-[2-(1H-indol-4-yloxy)-ethyl]-aminehydrochloride hhh)[5-(3-fluorophenyl)-pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)-ethyl]-aminemalonate iii)[5-(3-fluorophenyl)-pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)-ethyl]-aminehemifumarate jjj)[5-(3-fluorophenyl)-pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)-ethyl]-aminehemisulfate kkk)[5-(3-fluorophenyl)-pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)-ethyl]-aminetartrate lll)[5-(3,5-difluorophenyl)-pyridin-3-ylmethyl]-[2-(2-methyl-1H-indol-4-yloxy)-ethyl]-aminehemifumarate mmm)[5-(2-fluorophenyl)-pyridin-3-ylmethyl]-[2-(1H-indol-4-yloxy)-ethyl]-aminedihydrochloride nnn)[2-(1H-indol-4-yloxy)-ethyl]-[5-(3,4,5-trifluorophenyl)-pyridin-3-ylmethyl]-aminedihydrochloride ooo)[2-(1H-indol-4-yloxy)-ethyl]-(5-phenyl-pyridin-3-ylmethyl)-aminedihydrochloride or a corresponding free base or another tolerable saltor solvate of the corresponding free base.
 8. A compound of the formulaII:

R¹ is a heterocycle radical which is quinolyl or isoquinolyl optionallysubstituted by at least one chlorine, or indolyl, benzothiazolyl,coumaronyl, coumarinyl, pyridyl, or carbazolyl, wherein quinolyl,isoquinolyl, indolyl, or benzothiazolyl is optionally substituted with amethyl group or an ethoxycarbonyl group and the heterocycle radical isoptionally monosubstituted, disubstituted or trisubstituted by one ormore of the groups -A, —OR⁴, —N(R⁴)₂, —NO₂, —CN, Hal, —COOR⁴, —CON(R⁴)₂,—COR⁴, or ═O; R² is a phenyl group which is optionally monosubstituted,disubstituted, trisubstituted, tetrasubstituted or pentasubstituted byone or more of the groups Hal, -A, —O-A, —NO₂or —CN, or is a thienylgroup which is optionally monosubstituted or disubstituted by one ormore of the groups Hal, -A, —O-A, —NO₂, —CN or thienyl; R⁴ is H or —A; Ais C₁C₆-alkyl, where 1-7 hydrogen atoms are optionally replaced byfluorine; —X— is —O—, ——S—, sulfonyl, or —C)R⁴)₂—; —Y— is—[C(R⁴)₂]_(n)—; Hal is F, Cl, Br or I; and n is 1, 2, 3 or
 4. 9. Acompound according to claim 1, wherein R¹ is quinoline-7-yl orquinoline-8-yl, where a hydrogen is optionally replaced by a chlorineatom in position 5, or indol-4-yl or indol-7-yl, where a hydrogen inposition 2 of the quinolyl or indolyl is optionally replaced by a methylgroup or ethoxycarbonyl group.
 10. A compound according to claim 1,wherein R¹ is indol-4-yl, 2-methylindol-4-yl or quinolin-8-yl.
 11. Aprocess for the preparation of a compound of the formula I according toclaim 1, comprising: synthesizing a compound of the formula VI:

 from bromopyridin-3-ylmethanal and H₂N—Y—OH; synthesizing a compound ofthe formula V:

 from L—CO—O—K wherein K is tert-butyl, fluoren-9-ylmethyl or benzyl,and L is Cl, N₃ or tert-butoxycarbonyloxy; and a  compound of theformula VI:

synthesizing a compound of the formula IV:

 from R²—B(OH)₂ and a compound of the formula V:

synthesizing a compound of the formula III:

 from HX—R¹ and a compound of the formula IV:

 under the conditions of the Mitsunobu reaction; or synthesizing acompound of the formula II:

 from the compound of the formula III:


12. A compound of the formula IX:

R¹ is a heterocycle radical which is quinolyl or isoquinolyl optionallysubstituted by at least one chlorine, or indolyl, benzothiazolyl,coumaronyl, coumarinyl, pyridyl, or carbazolyl, wherein quinolyl,isoquinolyl, indolyl, or benzothiazolyl is optionally substituted with amethyl group or an ethoxycarbonyl group and the heterocycle radical isoptionally monosubstituted, disubstituted or trisubstituted by one ormore of the groups -A, —OR⁴, —N(R⁴)₂, —NO₂, —CN, Hal, —COOR⁴, —CON(R⁴)₂,—COR⁴, or ═O; R² is a phenyl group which is optionally monosubstituted,disubstituted, trisubstituted, tetrasubstituted or pentasubstituted byone or more of the groups Hal, -A, —O-A, —NO₂ or —CN, or is a thienylgroup which is optionally monosubstituted or disubstituted by one ormore of the groups Hal, -A, —O-A, —NO₂, —CN or thienyl; R⁴ is H or —A; Ais C₁C₆-alkyl, where 1-7 hydrogen atoms are optionally replaced byfluorine; —Y— is —[C(R⁴)₂]_(n)—; Hal is F, Cl, Br or I; and n is 1, 2, 3or
 4. 13. A process for preparing a compound of the formula I accordingto claim 1, comprising one of the following: synthesizing a compound ofthe formula XI:

 from a compound of the formula XII:

 and R²—B(OH)₂; synthesizing a compound of the formula X:

 from a compound of the formula XI; synthesizing a compound of theformula IX:

 from a compound of the formula X and R¹—O—Y—NH₂; synthesizing acompound NH₂—Y—O—R¹, identical to a compound of the formula XIII:

 where m is 1, 2 or 3, from a compound of the formula XIV:

 or synthesizing a compound of the XIV from a compound of the formulaXV:


14. A process for producing pharmaceutical preparation, comprisingconverting a compound according to claim 1 into a suitable dose formtogether with a suitable vehicle.
 15. A medicament comprising a compoundaccording to claim 1 and a pharmaceutically acceptable carrier.
 16. Amethod of treating an illness of the central nervous system comprisingadministrating an effective amount of a compound according to claim 1 toa patient in need thereof.
 17. A method according to claim 16, whereinthe illness is schizophrenia or a psychotic anxiety state.